BACE1 inhibition reprograms macrophages to promote their phagocytosis of cancer cells reducing glioblastoma progression.
Major Finding: BACE1 inhibition reprograms macrophages to promote their phagocytosis of cancer cells reducing glioblastoma progression.
Concept: Tumor-promoting macrophages are maintained by BACE1 activation of IL6-sIL6R-STAT3 signaling.
Impact: This study supports the repurposing of BACE1 inhibitors from Alzheimer's disease to cancer therapy.
Tumor-associated macrophages (TAM), when in high abundance, are associated with a poor prognosis in many tumor types including glioblastoma (GBM). Most TAMs located in the GBM microenvironment are tumor-promoting; therefore, reprogramming them into a more tumor-suppressive phenotype could improve therapy response. Zhai and colleagues, using a cell-based screen to detect small molecules able to activate TAM phagocytosis of GBM cells, identified an inhibitor targeting β-site amyloid precursor protein-cleaving enzyme 1 (BACE1; MK-8931), previously tested in clinical trials for Alzheimer disease. Treatment of GBM xenografts with MK-8931 led to an increase in TAM engulfment of glioma cells as compared with vehicle control as well as inhibited tumor growth and significantly extended survival of GBM xenograft-bearing mice. Additionally, MK-8931 induced apoptosis and reduced GBM cell proliferation in vivo. Further experiments revealed that treatment with the BACE1 inhibitor or genetic ablation of BACE1 induced a change in TAM phenotype, moving from a more tumor-promoting (M2) phenotype to one more tumor suppressive (M1), which aids in this BACE1-mediated suppression of tumor growth. Combination of MK-8931 with low-dose radiation, known to induce macrophage infiltration, further suppressed tumor growth and extended survival in mouse models. To elucidate how BACE1 promotes TAM polarization, the role of key transcriptional regulators of M2 polarization, STAT3 and STAT6, was investigated and showed that STAT3, but not STAT6, phosphorylation was significantly downregulated upon both genetic ablation or pharmacologic inhibition of BACE1, with ectopic expression of STAT3 rescuing the phenotype induced by BACE1 disruption or inhibition. STAT3 activation was determined to occur through BACE1 transmembrane protease activity where BACE1 cleaves IL6R into sIL6R activating the trans-IL6-sIL6R-STAT3 cascade. Moreover, investigation of clinical relevance revealed high BACE1 expression in GBM specimens was correlated with a worse prognosis. This study indicates the therapeutic promise of BACE1 in GBM through its effects on macrophage phagocytosis and polarization and suggests the repurposing of these inhibitors as an alternative to immunotherapy in cancers such as GBM.
Zhai K, Huang Z, Huang Q, Tao W, Fang X, Zhang A, et al. Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells. Nat Cancer 2021;2:1136–51.
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